Melanin concentrating hormone, or MCH, is a cyclic 19 amino acid neuropeptide that functions as a regulator of food intake and energy balance. MCH is produced in the hypothalamus of many vertebrate species including man. MCH is also produced at various peripheral sites, including the gastrointestinal tract and testis.
The postulated role of MCH in feeding behavior and body weight has been confirmed by the finding that I.C.V. injection of MCH into the lateral ventrical of the hypothalamus increases caloric consumption in rats over similarly treated control animals. Furthermore, rats having the ob/ob genotype exhibit a 50–80% increase in MCH mRNA expression as compared to leaner ob/+ genotype mice. MCH knockout mice are leaner than their MCH-producing siblings due to hypophagia and an increased metabolic rate.
MCH activity is mediated via binding to specific cell surface receptors. Like other G protein-coupled receptors (e.g., neuropeptide Y (NPY) and beta-adrenergic receptors), MCH receptors are membrane-spanning proteins that consist of a single contiguous amino acid chain comprising an extracellular N-terminal domain, seven membrane-spanning alpha helical domains (connected by three intracellular loop domains alternating with three extracellular loop domains), and an intracellular C-terminal domain. Signal transduction is initiated by the binding of MCH to the receptor. This binding is believed to elicit conformational changes in the extracellular domains. When the receptor is functioning properly, these conformational changes are believed to propagate through the transmembrane domains and result in a coordinated change in the intracellular portions of the receptor. This precise alteration in the intracellular domains is believed to trigger the associated G-protein complex to modulate intracellular signaling.
The human MCH type 1 receptor (MCH1R) is a 353 amino acid G protein-coupled receptor, first reported by Lakaye, et al. (BBA (1998) 1401:216–220), and described in U.S. Pat. No. 6,291,195. MCH1R has also been known as SLC-1 (somatostatin-like receptor; see U.S. Pat. No. 6,008,012). Immunohistochemistry studies of rat brain sections indicate that the MCH1R receptor is widely expressed in the brain. MCH1R receptor expression has been found in the olfactory tubercle, cerebral cortex, substantia nigra, basal forebrain CA1, CA2, and CA3 field of the hippocampus, amygdala, and in nuclei in the hypothalamus, thalamus, midbrain and hindbrain. Strong signals have been observed in the ventromedial and dorsomedial nuclei of the hypothalamus, two areas of the brain known to be involved in feeding behavior. Upon binding MCH, MCH1R expressed in HEK 293 cell mediates a dose dependent release of intracellular calcium. Cells expressing MCH receptors have also been shown to exhibit a pertussis toxin sensitive dose-dependent inhibition of forskolin-elevated cyclic AMP, suggesting that the receptor couples to a Gi/o G-protein alpha subunit.
Because MCH is an important regulator of food intake and energy balance, agents capable of modulating MCH receptor activity are highly desirable for the treatment of obesity, eating disorders (e.g., bulimia and anorexia), sexual disorders (e.g., anorgasmic or psychogenic impotence) and metabolic disorders, such as diabetes. Isolated MCH receptors (e.g., as components of membrane preparations), cells expressing such receptors and cloned MCH receptor genes are needed to facilitate the discovery of such agents.
Accordingly, there is a need in the art for the identification of additional MCH receptor sequences. The present invention fulfills this need, and provides further related advantages.